Intrathecal antibody production is a hallmark of multiple sclerosis and humoral immunity is thought to play an important role in the inflammatory response and development of demyelinated lesions. The presence of lymphoid follicle-like structures in the cerebral meninges of some multiple sclerosis patients indicates that B-cell maturation can be sustained locally within the CNS and contribute to the establishment of a compartmentalized humoral immune response. In this study we examined the distribution of ectopic B-cell follicles in multiple sclerosis cases with primary and secondary progressive clinical courses to determine their association with clinical and neuropathological features. A detailed immunohistochemical and morphometric analysis was performed on post-mortem brain tissue samples from 29 secondary progressive (SP) and 7 primary progressive (PP) multiple sclerosis cases. B-cell follicles were detected in the meninges entering the cerebral sulci of 41.4% of the SPMS cases, but not in PPMS cases. The SPMS cases with follicles significantly differed from those without with respect to a younger age at multiple sclerosis onset, irreversible disability and death and more pronounced demyelination, microglia activation and loss of neurites in the cerebral cortex. Cortical demyelination in these SPMS cases was also more severe than in PPMS cases. Notably, all meningeal B-cell follicles were found adjacent to large subpial cortical lesions, suggesting that soluble factors diffusing from these structures have a pathogenic role. These data support an immunopathogenetic mechanism whereby B-cell follicles developing in the multiple sclerosis meninges exacerbate the detrimental effects of humoral immunity with a subsequent major impact on the integrity of the cortical structures.

Recent studies have revealed extensive neocortical pathology in multiple sclerosis (MS). The hippocampus is a unique archaeocortical structure understudied in MS. It plays a central role in episodic and anterograde memory-the most frequently impaired cognitive modalities in MS. This histopathological study aimed to investigate inflammatory demyelination and neurodegenerative changes in the MS archaeocortex. A detailed quantitative analysis was performed on hippocampal autopsy tissue from 45 progressive MS cases and seven controls. Forty-one lesions were identified in 28 of the 45 hippocampal MS-blocks examined, with percentage area of demyelination averaging 30.4%. The majority of lesions were chronic and subpially or subependymally located. Compared to controls, neuronal numbers were decreased by 27% in CA1 and 29.7% in CA3-2. Furthermore, the size of neurones was decreased by 17.4% in CA1. There was evidence of gross hippocampal atrophy with a 22.3% reduction in the average cross-sectional area, which correlated with neuronal loss. Our study provides evidence of substantial archaeocortical pathology largely resembling patterns seen in the neocortex and suggests that hippocampal involvement could contribute to memory impairments often seen in MS.

Experimental studies using models of multiple sclerosis (MS) indicate that rapid and extensive remyelination of inflammatory demyelinated lesions is not only possible, but is the normal situation. The presence of completely remyelinated MS lesions has been noted in numerous studies and routine limited sampling of post mortem MS material suggests that remyelination may be extensive in the early stages but eventually fails. However, visual macroscopic guided sampling tends to be biased towards chronic demyelinated lesions. Here we have extensively sampled cerebral tissue from two MS cases to investigate the true extent of remyelination. Sections were cut from 185 cerebral tissue blocks and stained with haematoxylin and eosin (H&E), luxol fast blue and cresyl fast violet (LFB/ CFV) and anti-myelin oligodendrocyte glycoprotein, human leucocyte antigen-DR (HLA-DR) and 200 kDa neurofilament protein antibodies. Demyelinated areas were identified in 141 blocks, comprising both white matter (WMLs) and/or grey matter lesions. In total, 168 WMLs were identified, 22% of which were shadow plaques, 73% were partially remyelinated and only 5% were completely demyelinated. The average extent of lesion remyelination for all WMLs investigated was 47%. Increased density of HLA-DR + macrophages and microglia at the lesion border correlated significantly with more extensive remyelination. Results from this study of two patients with long standing disease suggest that remyelination in MS may be more extensive than previously thought.

Saltatory conduction in the nervous system is enabled through the intimate association between the leading edge of the myelin sheath and the axonal membrane to demarcate the node of Ranvier. The 186 kDa neuron specific isoform of the adhesion molecule neurofascin (Nfasc186) is required for the clustering of voltage gated Na+ channels at the node, whilst the 155 kDa glial specific isoform (Nfasc155) is required for the assembly of correct paranodal junctions. In order to understand the relationship between these vital structures and how they are affected in multiple sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of inflammation, demyelination and remyelination from post-mortem brains. Fourteen cases of neuropathologically confirmed multiple sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 demyelinating or remyelinating lesions, were used in this study. A significant early alteration in Nfasc155+ paranodal structures occurs within and adjacent to actively demyelinating white matter lesions that are associated with damaged axons. Shaker-type Kv1.2 channels, normally located distally to the paranode, overlapped with the disrupted Nfasc155+ structures. In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ nodes, indicating that complete disruption of the paranodal structure and movement of Kv1.2 channels precede alterations at the node itself. Within areas of partial remyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient oligodendrocyte-axonal contacts during the process of myelin repair or aberrant interactions. Within shadow plaques discretely clustered Na+v, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal nodal architecture. The alterations in oligodendrocyte Nfasc155 expression that accompany inflammation and demyelination suggest an ongoing disruption to the axonal-oligodendrocyte complex within newly forming as well as established lesions in multiple sclerosis, resulting in destruction of the Nfasc186+/Na+v nodal complex vital to successful fast neurotransmission in the CNS.

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